Sepsis, defined as the systemic host response to microorganisms in previously sterile tissues, is a syndrome related to severe infections and is characterized by end-organ dysfunction away from the primary site of infection. To meet the definition of sepsis, patients need to satisfy at least two of the Systemic Inflammatory Response Syndrome (SIRS) criteria in association with having a suspected or confirmed infection.
The clinical diagnostic parameters of septic patients as defined at the International Sepsis Definitions Conference in 2001 include the following (Levy et al. 2001):
aInfection (documented or suspected) and some(i.e., two or more) of the followingb:General parametersFever (core temperature >38.3° C.)Hypothermia (core temperature <36° C.Heart rate >90 bpm or >2 SD above the normal valuefor ageTachypnea: >30 bpmAltered mental statusSignificant edema or positive fluid balance (>20ml/kg over 24 h)Hyperglycemia (plasma glucose >110 mg/dl or 7.7mM/l) in the absence of diabetesInflammatory parametersLeukocytosis (white blood cell count >12,000/μl)Leukopenia (white blood cell count <4,000/μl)Normal white blood cell count with >10% immatureformsPlasma C reactive protein >2 SD above the normalvaluePlasma procalcitonin >2 SD above the normal valueHemodynamic parametersArterial hypotensionb (systolic blood pressure <90mmHg, mean arterial pressure <70 mmHg,or a systolic blood pressure decrease >40 mmHg inadults or <2 SD below normal for age)Mixed venous oxygen saturation >70%bCardiac index >3.5 1 min−1 m−2c,dOrgan dysfunction parametersArterial hypoxemia (PaO2/FIO2 <300)Acute oliguria (urine output <0.5 ml kg−1 h−1 or 45mM/l for at least 2 h)Creatinine increase ≧ 0.5 mg/dlCoagulation abnormalities (international normalizedratio >1.5 or activated partialthromboplastin time >60 s)Ileus (absent bowel sounds)Thrombocytopenia (platelet count <100,000/μl)Hyperbilirubinemia (plasma total bilirubin >4 mg/dlor 70 mmol/l)Tissue perfusion parametersHyperlactatemia (>3 mmol/l)Decreased capillary refill or mottlingaDefined as a pathological process induced by a microorganismbValues above 70% are normal in children (normally 75-80%) and should therefore not be used as a sign of sepsis in newborns or childrencValues of 3.5-5.5 are normal in children and should therefore not be used as a sign of sepsis in newborns or childrendDiagnostic criteria for sepsis in the pediatric population is signs and symptoms of inflammation plus infection with hyper- or hypothermia (rectal temperature >38.5° C. or <35° C.), tachycardia (may be absent in hypothermic patients) and at least one of the following indications of altered organ function: altered mental status, hypoxemia, elevated serum lactate level, and bounding pulses
The normal host response to infection is complex, aiming to both identify and control pathogen invasion and start immediate tissue repair. Both the cellular and humoral immune systems are activated, giving rise to anti-inflammatory and proinflammatory responses. Exacerbating these mechanisms can cause a chain of events that leads to massive liberation of mediators with diffuse endothelial injury, tissue hypo-perfusion, disseminated intravascular coagulation, and refractory shock and eventually progression of a multiple organ dysfunction syndrome (MODS) and possibly death. FIG. 1 shows the main pathologic mechanisms in the early and later phases of MODS.
While almost any microorganism can be associated with sepsis and septic shock, Gram-negative bacteria are common etiologic pathogens. Lipopolysaccharides (LPS) are normal components of the cell wall of Gram-negative bacteria and have been recognized for many years as key risk factors in the development of septic shock syndrome. Many of the adverse effects of LPS in mammals are dependent on the activation of cellular and soluble inflammatory mediators including polymorphonuclear leukocytes (PMNs), and cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1). It has been shown that PMNs accumulate in tissues after LPS administration, and although they play an important role as a host defense mechanism, they are responsible for mediating LPS-induced tissue injuries. Several lines of evidence now suggested that stimulatory inflammatory cells release a plethora of mediators including reactive oxygen species, proteolytic enzymes and products of lipid peroxidation products.
Morbidity and mortality remain unacceptably high despite increasing knowledge about the pathophysiological pathways and processes involved in sepsis and improved hospital care. It still is one of the most prevalent causes of intensive care units (ICU) morbidity and mortality worldwide. More than 750,000 sepsis cases occur in the United States every year, leading to approximately 220,000 deaths; similar incidences have also been reported in Europe and around the world. In fact, the mortality rates of septic shock could be as high as 50% or up to 75% on longer follow-ups.
Clinical management usually begins with prompt recognition, determination of the probable infection site, early administration of antibiotics, low-dose corticosteroids, and resuscitation protocols. Corticosteroids, the most potent anti-inflammatory class of drugs, have demonstrated a modest decrease in mortality (absolute reduction of 10%) with lower doses in septic shock. Other anti-inflammatory drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) did not show to be helpful in ameliorating sepsis syndrome.
Furthermore, in attempts to find efficacious drugs that reduce mortality, a large number of immunomodulatory agents have been studied in experimental and clinical settings. However, the vast majority of these trials showed little success in reducing the overwhelmingly high mortality rates of septic shock patients. Only one immunomodulatory drug, drotrecogin alfa (a recombinant form of human activated protein C, Xigris®) has been approved as an adjunct to standard care in sepsis patients with evidence of organ dysfunction. The improved survival rate is also clinically modest, and only some patients with severe disease will benefit. The PROWESS trial, which suffered from few flaws, indicated a 6% absolute decrease in mortality rate (19% relative risk reduction) compared to placebo; this difference is somewhat remarkable considering that no other adjunctive treatment modality directed at underlying pathology (including TNF-α monoclonal antibodies, IL-1 antagonists, and p55 TNF receptor IgG1 fusion protein) has been shown to significantly alter clinical outcome in severe sepsis. Later studies reported that drotrecogin alfa is not effective in patients with a low risk of death or in pediatric patients. Administration of drotrecogin alfa is associated with an increased risk. In addition, a post hoc analysis of a subgroup of patients who had undergone recent surgery (i.e., within 30 days before enrolment) and had single-organ dysfunction indicated that the patients in this subgroup who received drotrecogin alfa had higher 28-day mortality rates than did the patients in this group who received placebo (20.7% vs. 14.1%, P=0.03). In response to these results and further analysis of the PROWESS data which suggested a lesser efficacy in surgical patients, an additional warning was introduced to the prescribing information for drotrecogin alfa, stating that the drug should not be used in patients with recent surgery and single organ dysfunction.
These findings and experiences indicate that the pathogenesis of sepsis syndrome is highly complex, and it involves multiple immune responses including the activation of cytokines and the generation of reactive free radicals. Therefore, it is important to continue the development of newer agents to potentially identify a clinically relevant anti-sepsis drug.
Thus, the object of the present invention is to provide new means and methods which are useful in the prevention and/or treatment of sepsis syndrome.